Project Summary/Abstract: The strong correlation between the number of aromatic rings in a drug candidate and the candidate?s likely attrition during development has led to the pursuit of replacements for phenyl moieties, giving rise to medicinal compounds containing alicycles. However, current small ring bioisosteres for phenyl groups are not amenable to facile derivatization, hindering their incorporation into drug candidates. Further, with the known bioisosteres utilized as alicyclic bridges in molecules, only a limited portion of spatial length is covered compared to that encompassed by phenyl and biphenyl units. As such, designing C(sp3)-enriched molecules with innovative structural properties is limited not only by the difficulty in synthesizing alicyclic isosteres, but also by the abridged spatial diversity achieved when employing these molecules in bioactive compounds. Thus, an easily accessible alicyclic compound that provides structural diversity in both 3-dimensional vectoral space and length would reveal new opportunities for molecular design. An alicyclic motif fulfilling spatial and vectoral requirements necessary for a phenylene bioisostere is 1,1?- bicyclobutyl; however, this species is currently absent from the synthetic literature. Preliminary results from the Chirik laboratory indicate that this architecture can be synthesized in one step from feedstock dienes and alkenes by (PDI)Fe-catalyzed [2+2] cascade cyclization (PDI = pyridinediimine). Herein, this proposal focuses on the expedient, modular synthesis of new 1,1?-bicyclobutyl isosteres as well as their derivatization relevant to incorporation into druglike molecules. Aim 1 details procedures to control chain length during the oligomerization process to selectively produce 1,1?-bicyclobutyl structures. Further, increases to reaction chemoselectivity and rate will be examined by installing hemilabile groups on the (PDI)Fe backbone. The potential for controlled derivatization of the resultant vinyl 1,1?-bicyclobutyls is explored in Aim 2, in which vinylcyclobutanes will be exploited as model systems en-route to functionalization of 1,1-bicyclobutyls. Here, (PDI)Fe-catalyzed hydrofunctionalization at the vinyl position provides a one-pot methodology for the construction and derivatization of cyclobutane cores; complementary functionalization at the opposite terminus of the cyclobutane structure will be conducted through expansion of the scope of alkene oligomerization partner to include synthetically useful boranes. In Aim 3, the core atoms in the framework of the bicyclobutyl will be altered through the [2+2] oligomerization of dienes and aldimines or nitriles mediated by (PDI)Fe catalysts. The regioselectivity of the oxidative cyclization event prevents opportunities for installing a nitrogen atom at either the 2? or 3? position of the core, providing otherwise inaccessible modularity in the vectoral disposition of the structure. The synthetic protocols established in this work will afford modular routes to unprecedented alicyclic frameworks using a unified, base metal-catalyzed system. These synthetic ventures will access a completely novel bioisosteric candidate, leading to a direct impact on medicinal chemistry in the realm of molecular design.